RESEARCH FOCI

Liver disease is an important clinical problem, impacting over 30 million Americans and over 600 million people worldwide and is the 12th leading cause of death in the United States and 16th worldwide. Models of human liver disease have been historically limited to rodent models or studies in immortalized human cell lines that do not faithfully recapitulate human liver phenotype and function. The Schwartz Lab will focus on building models of human liver disease in vitro. We will use stem cell biology and incorporate engineering techniques to better understand human liver disease with the goal to improve clinical therapy.

Pluripotent Stem Cells and Hepatocyte Development

Induced pluripotent stem cells can be routinely generated from easily accessible tissues, such as blood and skin, in a process of cellular reprogramming. They are easily grown, scalable, and can in a developmentally appropriate and efficient manner be differentiated towards the hepatocyte lineage. iPS derived hepatocyte-like cells not only express hepatocyte-specific markers but also have hepatocyte function, i.e. secrete serum proteins and have cytochrome P450 activity. However, current protocols fall short of producing a bonafide “adult” hepatocyte as iPS derived hepatocyte-like cells phenotype and function is more consistent with fetal hepatocytes. The current state of the art does not enable the production of mature terminally differentiated hepatocytes, likely due to the limitations of working in vitro and our lack of understanding of hepatocyte development (fetal to adult). We have used several approaches to identify the determinants of hepatocyte terminal differentiation: 1) Small Molecule Screen 2) Cellular organization during differentiation 3) Role of the microenvironment 4) Development of Cellular reporters of differentiation

Models systems that allow dissection of the interplay between viral infection and host genetics are limited. Consequently the role that host genetics play in clinical disease are unclear. To address this gap, our group has developed and shown that pluripotent stem cell derived hepatocyte-like cells can be used to study infectious disease. We have used this system to study the life cycle of several hepatrophic infections. Pluripotent stem cell lines generated with a variety of genetic variants will be used to explore the impact that genetic variants play in infectious disease.